tbuckley/cabot-search huggingface dataset:
First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Authors: Tae Won Kim, Howard A. Burris, Maria J. de Miguel Luken, Michael J. Pishvaian, Yung-Jue Bang, Michael Gordon, Ahmad Awada, D. Ross Camidge, F. Stephen Hodi, Grant A. McArthur, Wilson H. Miller, Andres Cervantes, Laura Q. Chow, Alexander M. Lesokhin, Annemie Rutten, Mario Sznol, Deepali Rishipathak, Shang-Chiung Chen, Eric Stefanich, Tony Pourmohamad, Maria Anderson, Jeong Kim, Mahrukh Huseni, Ina Rhee, Lillian L. Siu
Journal: Clinical Cancer Research (2022)

OX40, a receptor transiently expressed by T cells upon antigen recognition, is associated with costimulation of effector T cells and impairment of regulatory T-cell function. This first-in-human study evaluated MOXR0916, a humanized effector-competent agonist IgG1 monoclonal anti-OX40 antibody.Eligible patients with locally advanced or metastatic refractory solid tumors were treated with MOXR0916 intravenously once every 3 weeks (Q3W). A 3+3 dose-escalation stage (0.2-1,200 mg; n = 34) was followed by expansion cohorts at 300 mg (n = 138) for patients with melanoma, renal cell carcinoma, non-small cell lung carcinoma, urothelial carcinoma, and triple-negative breast cancer.MOXR0916 was well tolerated with no dose-limiting toxicities observed. An MTD was not reached. Most patients (95%) experienced at least one adverse event (AE); 56% of AEs, mostly grade 1-2, were related to MOXR0916. Most common treatment-related AEs included fatigue (17%), diarrhea (8%), myalgia (7%), nausea (6%), decreased appetite (6%), and infusion-related reaction (5%). Pharmacokinetic (PK) parameters were dose proportional between 80 and 1,200 mg and supported Q3W administration. The recommended expansion dose based on PK and OX40 receptor saturation was 300 mg Q3W. Immune activation and upregulation of PD-L1 was observed in a subset of paired tumor biopsies. One renal cell carcinoma patient experienced a confirmed partial response. Overall, 33% of patients achieved stable disease.Although objective responses were rarely observed with MOXR0916 monotherapy, the favorable safety profile and evidence of tumor immune activation in a subset of patients support further investigation in combination with complementary agents such as PD-1/PD-L1 antagonists.
Abstract 2440: Investigating the role of Eya3 in the regulation of NF-kB signaling and tumor progression in TNBC
Authors: Connor J. Hughes, Rebecca Mallo, Kaiah Fields, Hengbo Zhou, Annika Gustafson, Deguang Kong, Jill Slansky, Rui Zhao, Heide L. Ford
Journal: Cancer Research (2022)

Abstract Triple Negative Breast Cancer (TNBC), characterized by low/absent expression of the estrogen receptor and the HER2 growth factor receptor, has high rates of metastasis and an overall poor prognosis largely due to a lack of targeted therapeutic options. The Eyes absent (Eya) family of proteins are transcriptional cofactors with both intrinsic tyrosine phosphatase and associated serine/threonine phosphatase activities. In addition to developmental functions, Eyas have been shown to play a role in promoting many hallmarks of cancer. Published work from our laboratory demonstrated that Eya3 is capable of upregulating expression of PD-L1 in TNBC tumors thereby suppressing anti-tumor CD8+ T-cell responses, and preliminary data suggests that Eya3 may also regulate the expression of various cytokines in this context. In tumor cells, innate immune signaling pathways, such as NF-kB, have been shown to promote tumor progression, immune evasion, and metastasis in many distinct tumor types. We hypothesize that, in addition to regulating CD8+ T-cell responses, Eya3 regulates innate immune signaling in TNBC cells to facilitate enhanced primary tumor growth and metastasis. Preliminary findings suggest that Eya3 is a key mediator of tumor progression and metastasis in TNBC and a strong regulator of NF-kB signaling in this context. Further exploration is warranted to determine the mechanism through which Eya3 regulates these phenotypes, whether Eya3-mediated NF-kB activation is a major contributor to the pro-metastatic phenotype of Eya3, and whether Eya3 could serve as a therapeutic target for preventing or treating disseminated TNBC. Citation Format: Connor J. Hughes, Rebecca Mallo, Kaiah Fields, Hengbo Zhou, Annika Gustafson, Deguang Kong, Jill Slansky, Rui Zhao, Heide L. Ford. Investigating the role of Eya3 in the regulation of NF-kB signaling and tumor progression in TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2440.
Kidney Denervation Results in Lasting Blood Pressure Control
Authors: Anita Slomski
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 1578: Interaction of E-cadherin and EGFR in the collective cell migration of colon cancer cells
Authors: Viriya Adhiguna Winarso, Yi-Wen Lu, Yu-Cheng Weng, Xiang-Ling Hou, Hui Min Koo, Yu-n Li, Wei-Ting Chao
Journal: Cancer Research (2022)

Abstract Collective cell migration is one of the most important cellular events where a cluster of cells moves together in a coordinated way. Many studies have found this phenomenon as the hallmark of cancer progression and metastasis. In epithelial single cell migration, downregulation of adherens junction (AJ) molecule E-cadherin occurs at the initial step known as the Epithelial to Mesenchymal Transition (EMT). However, in collective cell migration, E-cadherin junction is maintained to provide adhesion between cells. Moreover, it also mediates the cell-cell intercommunication that is critical, for instance, to alter the group polarization through actin cytoskeleton remodeling. Interestingly, Epidermal Growth Factor Receptor (EGFR) was found to colocalize with E-cadherin in the cell-cell contact region, implicating that E-cadherin and EGFR might interact in the cell junction of collective cell migration. To address this, a human colorectal cancer cell line exhibiting epithelial phenotype HT-29 was used. The cell density and calcium presence were modified to infer the effect of differential expression and stability of E-cadherin on the cellular signaling of proliferation and migration. The results showed that stable and enhanced expression of E-cadherin downregulates EGFR expression and reduces its activity. Moreover, the Src phosphorylation increased when the cell-cell contact was strengthened via calcium addition and decreased when the cell-cell contact was diminished via calcium chelation. Overall, this indicates that E-cadherin expression at the cell-cell junction and contact stability determine the EGFR expression, activity, and Src phosphorylation. With the goal of deciphering the relationship of E-cadherin and EGFR in cell contact, proliferation, and migration, we intend to finally implement the knowledge as a strategy or approach in promoting alternative methods to inhibit metastasis. Citation Format: Viriya Adhiguna Winarso, Yi-Wen Lu, Yu-Cheng Weng, Xiang-Ling Hou, Hui Min Koo, Yu-n Li, Wei-Ting Chao. Interaction of E-cadherin and EGFR in the collective cell migration of colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1578.
Abstract 5984: MT1-MMP cooperates with TGF-beta receptor-mediated signaling to trigger SNAIL and induce epithelial-to-mesenchymal-like transition in U87 glioblastoma cells
Authors: Souad Djediai, Narjara Gonzalez Suarez, Zoé Joly-Lopez, Borhane Annabi
Journal: Cancer Research (2022)

Abstract Transforming growth factor (TGF)-β triggers metastasis through epithelial-to-mesenchymal transition (EMT) to which a role for a membrane type-1 matrix metalloproteinase (MT1-MMP) has been associated. While EMT cooperates with MMP activity in glioblastoma multiforme, the molecular crosstalk between TGF-β signaling and MT1-MMP however remains poorly understood. Here, the existence of common EMT biomarkers, induced through TGF-β and MT1-MMP inducer Concanavalin A (ConA), was explored using RNA-seq analysis and differential gene arrays in human U87 glioblastoma cells. TGF-β and ConA triggered SNAIL and Fibronectin expressions in a dose-dependent manner. Those inductions were antagonized by the TGF-β receptor kinase inhibitor Galunisertib, the JAK/STAT inhibitors AG490 and Tofacitinib, and by the diet-derived epigallocatechin gallate (EGCG). Transient gene silencing of MT1-MMP prevented the induction of SNAIL by ConA and abrogated TGF-β-induced cell chemotaxis. Moreover, ConA induced STAT3 and Src phosphorylation suggesting these pathways to be involved in the MT1-MMP-mediated signaling axis that led to SNAIL induction. Our findings highlight a new signaling axis linking MT1-MMP to TGF-β-mediated EMT-like induction in glioblastoma cells, which process can be prevented by the diet-derived EGCG Citation Format: Souad Djediai, Narjara Gonzalez Suarez, Zoé Joly-Lopez, Borhane Annabi. MT1-MMP cooperates with TGF-beta receptor-mediated signaling to trigger SNAIL and induce epithelial-to-mesenchymal-like transition in U87 glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5984.
Abstract 1133: Novobiocin-mediated polymerase theta inhibition induces cGAS/STING pathway activation and T-cell infiltration in BRCA-associated cancers
Authors: Jeffrey Patterson-Fortin, Heta Jadhav, Tin Phan, Alan D'Andrea, Geoffrey I. Shapiro
Journal: Cancer Research (2022)

Abstract Recently developed inhibitors of polymerase theta have demonstrated synthetic lethality in pre-clinical tumor models of BRCA-associated cancers. Given that other DNA damage repair inhibitor therapies, including PARP inhibitors, induce changes in the tumor immune microenvironment, we asked whether polymerase theta inhibition would also alter the tumor microenvironment in BRCA-associated cancers. We have demonstrated that novobiocin, a first-in-class inhibitor of the polymerase theta ATPase domain, induces both innate and adaptive immune responses through activation of the cGAS/STING pathway in BRCA-deficient tumor cells. Novobiocin-mediated polymerase theta inhibition generates micronuclei, activating the cGAS/STING pathway in both BRCA1-deficient MDA-MB-436 triple-negative breast cancer and BRCA2-deficient CAPAN1 pancreatic cancer models in vitro. Activation of the STING pathway upregulated the expression of interferon response genes, which was abrogated upon siRNA-mediated STING depletion. As an adaptive response, novobiocin also increased expression of PD-L1 in BRCA-deficient tumor cells. These effects were not observed in isogenic cell lines in which wild-type BRCA expression was corrected by add-back. Using a genetically engineered syngeneic mouse model of BRCA1-deficient breast cancer, we confirmed novobiocin-mediated activation of the cGAS/STING pathway in vivo, resulting in the induction of pro-inflammatory signaling and ultimately robust CD8+ T-cell infiltration and activation. Taken together, our findings demonstrate that novobiocin-mediated polymerase theta inhibition induces local and systemic immune responses in a cGAS/STING-dependent manner and provide a rationale for combining polymerase theta inhibition with immunotherapies for the treatment of BRCA-associated cancers. Citation Format: Jeffrey Patterson-Fortin, Heta Jadhav, Tin Phan, Alan D'Andrea, Geoffrey I. Shapiro. Novobiocin-mediated polymerase theta inhibition induces cGAS/STING pathway activation and T-cell infiltration in BRCA-associated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1133.
Delivery of an ectonucleotidase inhibitor with ROS-responsive nanoparticles overcomes adenosine-mediated cancer immunosuppression
Authors: Chengqiong Mao, Stacy Yeh, Juan Fu, Mercedes Porosnicu, Alexandra Thomas, Gregory L. Kucera, Konstantinos I. Votanopoulos, Shaomin Tian, Xin Ming
Journal: Science Translational Medicine (2022)

Tumor evasion of immune destruction is associated with the production of immunosuppressive adenosine in the tumor microenvironment (TME). Anticancer therapies can trigger adenosine triphosphate (ATP) release from tumor cells, causing rapid formation of adenosine by the ectonucleotidases CD39 and CD73, thereafter exacerbating immunosuppression in the TME. The goal of this study was to develop an approach to facilitate cancer therapy–induced immunogenic cell death including ATP release and to limit ATP degradation into adenosine, in order to achieve durable antitumor immune response. Our approach was to construct reactive oxygen species (ROS)–producing nanoparticles that carry an ectonucleotidase inhibitor ARL67156 by electronic interaction and phenylboronic ester. Upon near-infrared irradiation, nanoparticle-produced ROS induced ATP release from MOC1 cancer cells in vitro and triggered the cleavage of phenylboronic ester, facilitating the release of ARL67156 from the nanoparticles. ARL67156 prevented conversion of ATP to adenosine and enhanced anticancer immunity in an MOC1-based coculture model. We tested this approach in mouse tumor models. Nanoparticle-based ROS-responsive drug delivery reprogramed the immunogenic landscape in tumors, eliciting tumor-specific T cell responses and tumor regression, conferring long-term survival in mouse models. We demonstrated that TME reprograming sets the stage for response to anti-programmed cell death protein 1 (PD1) immunotherapy, and the combination resulted in tumor regression in a 4T1 breast cancer mouse model that was resistant to PD1 blockade. Furthermore, our approach also induced immunological effects in patient-derived organotypic tumor spheroid model, suggesting potential translation of our nanoparticle approach for treating human cancers.
Abstract 3754: 5-Hydroxymethylcytosine (5hmC) at or near Pathogenic Variant Hot Spots as Potential Targets for Early Cancer Detection
Authors: Yabin Lu, Michael Lu
Journal: Cancer Research (2022)

Abstract Since 5-hydroxymethylcytosine (5hmC) emerged as an intermediate metabolite in active DNA demethylation, there have been increasing efforts to elucidate its function as a stable modification of the genome. In the current study, we demonstrate that discrete 5hmc sites within 80bp hotspot regions exist in a greater proportion of cancer versus normal cells. 5hmc was detected in 16 of 17 known hotspots having C to T or G to A mutations. The results show the presence of two characteristically distinct 5hmc groups: Tier 1 Group with 3 to 8-fold more 5hmcs detected in tumor-cells than in normal-cell derived DNA (as observed in 6 of 11 CpG sites). Tier 2 group with equal allele frequency of 5hmc among normal and tumor-cell derived DNA at 5 CpG hotspot sites as well as 5 non-CpG hotspots. Thus, detection and quantification of the Tier 1 group of 5hmc sites or its prevalence at or near cancer mutation hot spots in cells may enable early detection, screening and potentially prediction of the likelihood of cancer occurrence or the severity of the cancer. Citation Format: Yabin Lu, Michael Lu. 5-Hydroxymethylcytosine (5hmC) at or near Pathogenic Variant Hot Spots as Potential Targets for Early Cancer Detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3754.
Facts and Hopes in the Relationship of EBV with Cancer Immunity and Immunotherapy
Authors: Baochun Zhang, Il-Kyu Choi
Journal: Clinical Cancer Research (2022)

Epstein-Barr virus (EBV), the first identified human tumor virus, infects and takes up residency in almost every human. However, EBV genome-positive tumors arise in only a tiny minority of infected people, presumably when the virus-carrying tumor cells are able to evade immune surveillance. Traditional views regard viral antigens as the principal targets of host immune surveillance against virus-infected cells. However, recent findings indicate that EBV-infected/-transformed B cells elicit both cytotoxic CD8+ and CD4+ T-cell responses against a wide range of overexpressed cellular antigens known to function as tumor-associated antigens (TAA), in addition to various EBV-encoded antigens. This not only broadens the ways by which the immune system controls EBV infection and prevents it from causing cancers, but also potentially extends immune protection toward EBV-unrelated cancers by targeting shared TAAs. The goal of this review is to incorporate these new findings with literature data and discuss future directions for improved understanding of EBV-induced antitumor immunity, as well as the hopes for rational immune strategies for cancer prevention and therapy.
Abstract 5967: ROSA: An ambassador program facilitating bidirectional partnerships between communities and basic scientists
Authors: Gabriela Ruiz, Amanda Lee
Journal: Cancer Research (2022)

Abstract Background: Community Outreach and Engagement (COE) is integral in NCI-designated Cancer Centers. COEs work with community stakeholders identifying community needs, communicating research, and catalyzing significant activities to Cancer Center’s catchment areas. To facilitate this, the University of Arizona Cancer Center (UACC) Office of COE established the Research Outreach for Southern Arizona (ROSA) program, supporting bidirectional partnerships between basic scientists and underrepresented communities in catchment areas. Objective: To describe a community and student ambassador program developed as ROSA, bridging gaps between basic science programs and community needs in UACC catchment areas. Methods: The UACC catchment areas include five southern Arizona counties where 40% of residents are Hispanic, compared to 18.3% in the US. Moreover, ambassadors were bilingual/bicultural Hispanic undergraduate students (n=4) and Hispanic community members (n=4). The ambassador program held weekly cancer educational discussions, research methods, monthly Meet the Scientist events, and presentations on experiences. Evaluations for ROSA were completed by all affiliates. Results: Overall, ROSA ambassadors reported increased knowledge of research and increased confidence sharing cancer information. Facilitators of ROSA community members included a bilingual/bicultural team, outreach collaborations, and participant compensation. Barriers included payments for undocumented members, lack of Spanish-speaking scientists, and reduced in-person activities. As a result of ROSA partnerships, scientists, healthcare professionals, and stakeholders is developing Scientific Cafes where scientists present research proposals for community feedback. The workgroup will select a community-driven project to implement in the future. Discussion: Based on positive ambassador evaluations and working group collaborations, ROSA is successful in growing authentic partnerships between scientists and communities. Recently, a community-based survey was developed by members to examine perceptions of cancer and willingness of clinical research participation. This survey will inform how basic scientists align research within community needs. ROSA will continue to be valuable in providing bidirectional engagement from basic scientists and community members in cancer research. Citation Format: Gabriela Ruiz, MEd., Amanda Lee. ROSA: An ambassador program facilitating bidirectional partnerships between communities and basic scientists [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5967.
Abstract LB557: Multiphoton phosphorescence quenching microscopy reveals kinetics of tumor oxygenation during anti-angiogenesis and angiotensin signaling inhibition
Authors: John Martin, Ryan Lanning, Dai Fukumura, Timothy Padera, Rakesh Jain
Journal: Cancer Research (2022)

Abstract Purpose: The abnormal function of tumor blood vessels causes hypoxia fueling disease progression and conferring treatment resistance. The local level of oxygen experienced by a cell will determine its response, making it critical to understand tissue oxygen levels with a spatial resolution on the order of the size of a cell. While microenvironment normalization strategies alleviate global hypoxia, how local oxygen levels change are not known because there are no in vivo techniques to longitudinally assess tumor vessels and interstitial oxygen in tumors with sufficient resolution. Understanding the heterogeneity of oxygen levels after microenvironmental normalization will help improve the efficacy of various normalization strategies. Experimental Design: We developed a multiphoton phosphorescence quenching microscopy system using a low-molecular weight palladium porphyrin probe to measure perfused vessels, oxygen tension and their spatial correlations in vivo in mouse skin, bone marrow, and tumors. Further, we measured the temporal and spatial changes in oxygen and vessel perfusion in tumors in response to microenvironmental normalization. Results: We found that vessel function was highly dependent on tumor type. Although some tumors had vessels with greater oxygen carrying ability than normal skin, most tumors had inefficient vessels. Further, inter-vessel heterogeneity in tumors coincided with heterogeneous response to microenvironmental normalizing agents. Using both vascular and stromal normalizing agents, we show that spatial heterogeneity in oxygen levels persist, even with global reductions in hypoxia. Conclusions: We present the first study to examine the high-resolution spatial and temporal response of tumor vessels to two agents known to improve vascular perfusion globally. Our measurements demonstrate that the heterogeneities in the local imbalance of pro- and anti-angiogenic signaling lead to spatially heterogeneous changes in vessel structure and function. Microscale dynamic vascular changes should be considered in optimizing the dose and schedule of microenvironment normalizing therapies to improve function. Citation Format: John Martin, Ryan Lanning, Dai Fukumura, Timothy Padera, Rakesh Jain. Multiphoton phosphorescence quenching microscopy reveals kinetics of tumor oxygenation during anti-angiogenesis and angiotensin signaling inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB557.